Introduction
Background
Red blood cells contain 4 hemoglobin chains. Each hemoglobin molecule is composed of 4 polypeptide chains associated with 4 heme groups. The heme group contains an iron molecule in the reduced or ferrous form (Fe2+). In this form, iron can combine with oxygen, by sharing an electron, to form oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state. Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin loses an electron and becomes oxidized, it is converted to the ferric state (Fe3+) or methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport. Because red blood cells are continuously exposed to various oxidant stresses, blood normally contains approximately 1% methemoglobin levels.
This low level of methemoglobin is maintained by 2 important mechanisms. One protective mechanism against oxidizing agents is the hexose-monophosphate shunt pathway within the erythrocyte. Through this pathway, oxidizing agents are reduced by glutathione prior to the formation of methemoglobin. The second and more important mechanism against methemoglobin formation uses 2 enzyme systems, diaphorase I and diaphorase II.
These 2 enzyme systems require nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively, to reduce methemoglobin to its original ferrous state. Diaphorase II quantitatively contributes only a small percentage of the red blood cells reducing capacity. However, diaphorase II can be pharmacologically activated by exogenous cofactors (ie, methylene blue) to 5 times its normal level of activity. Traditionally, methemoglobinemia is considered an acquired disorder; however, a very small number of congenital cases are also reported in the literature.
Pathophysiology
Oxidation of iron to the ferric state reduces the oxygen-carrying capacity of hemoglobin and produces a functional anemia. In addition, a ferric heme group affects nearby ferrous heme groups. Ferric heme groups impair the release of oxygen from nearby ferrous heme groups on the same hemoglobin tetramer. The result of methemoglobinemia is that oxygen delivery to tissues is impaired and the oxygen hemoglobin dissociation curve shifts to the left.
Organs with high oxygen demands (ie, CNS, cardiovascular system) usually are the first systems to manifest toxicity. Oxygenated blood is red, deoxygenated blood is blue, and blood-containing methemoglobin is a dark reddish brown color. This dark hue imparts clinical cyanosis when methemoglobin levels are at 1.5 g/dL (approximately 10-15% methemoglobin concentration); however, a level of 5 g/dL of deoxygenated blood is required for similar effects. Therefore, when methemoglobin levels are relatively low, cyanosis may be observed without cardiopulmonary symptoms.
Mortality/Morbidity
As methemoglobin levels increase, patients demonstrate evidence of cellular hypoxia. Death occurs when methemoglobin fractions approach 70%. Death can occur at lower levels in patients with significant comorbidities.
Race
The color change of the skin may be harder to detect in patients with darker skin color.
Age
- Children, especially those younger than 4 months, are particularly susceptible to methemoglobinemia.
- The primary erythrocyte protective mechanism against oxidative stress is the NADH system. In infants, this system has not fully matured, and the NADH methemoglobin reductase activity and concentrations are low.
Clinical
History
- Normal methemoglobin concentrations are 1% (range, 0-3%).
- At concentrations of 3-15%, a slight discoloration (eg, pale, gray, blue) of the skin may be present.
- At fractions of 15-20%, the patient may be relatively asymptomatic, but cyanosis is likely to be present.
- Signs and symptoms at fractions of 25-50% are as follows:
- Headache
- Dyspnea
- Lightheadedness, even syncope
- Weakness
- Confusion
- Palpitations, chest pain
- Signs and symptoms at fractions of 50-70% are as follows:
- Cardiovascular
- Abnormal cardiac rhythms
- CNS
- Altered mental status
- Delirium, seizures, coma
- Metabolic
- Profound acidosis
- Cardiovascular
Physical
- Discoloration of the skin and blood is the most striking physical finding.
- Cyanosis occurs with the formation of 1.5 g/dL of methemoglobin, as compared to 5 g/dL of deoxygenated hemoglobin.
- Seizures
- Coma
- Dysrhythmias (eg, bradyarrhythmia, ventricular dysrhythmia)
- Acidosis
- Cardiac or neurologic ischemia
Causes
- Compromised physiologic cellular defenses against oxidant stress occur in some patients, including the following:
- Children younger than 4 months may have underdeveloped protective mechanisms (NADH methemoglobin reductase). Infections, especially GI infections, may cause a buildup of systemic oxidants by an overgrowth of gut bacteria.
- Congenital lack of protective cellular capabilities includes those with the following:
- Patients with NADH methemoglobin reductase (diaphorase I) deficiency may develop congenital methemoglobinemia.
- Patients with hemoglobin M disease may have abnormal hemoglobin that is not amenable to reduction.
- Patients with pyruvate kinase deficiency may have an impaired glycolytic pathway, which results in deficient NADH production.
- Patients with G-6-PD deficiency may have impaired production of NADPH in the hexose-monophosphate shunt.
- Agents that inflict large oxidant stress on patients include the following:
- Pharmaceutical agents include local anesthetic agents (eg, benzocaine,1,2 lidocaine, prilocaine), amyl nitrite, chloroquine, dapsone,2 nitrates, nitrites, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, primaquine, quinones, and sulfonamides.
- Dapsone and its hydroxylamine metabolite can cause prolonged methemoglobinemia due to long half-lives.
- Environmental agents include the following:
- Aniline dyes
- Aromatic amines
- Arsine
- Butyl nitrite
- Chlorates
- Chlorobenzene
- Chromates
- Combustion products
- Dimethyltoluidine
- Foods containing nitrates or nitrites (including well water)
- Isobutyl nitrite
- Naphthalene
- Nitroaniline
- Nitrobenzene
- Nitrofurans
- Nitrophenol
- Nitrosobenzene
- Resorcinol
- Silver nitrate
- Trinitrotoluene
- Pharmaceutical agents include local anesthetic agents (eg, benzocaine,1,2 lidocaine, prilocaine), amyl nitrite, chloroquine, dapsone,2 nitrates, nitrites, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, primaquine, quinones, and sulfonamides.
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| Multimedia: Methemoglobinemia |
| References |
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References
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Ellenhorn MJ, Barceloux DG. Nitrates, nitrites, and methemoglobinemia. In: Medical Toxicology, Diagnosis and Treatment of Human Poisonings. 1988:844-851.
Fitzsimons MG, Gaudette RR, Hurford WE. Critical rebound methemoglobinemia after methylene blue treatment: case report. Pharmacotherapy. Apr 2004;24(4):538-40. [Medline].
Henretig FM, Gribetz B, Kearney T, Lacouture P, Lovejoy FH. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988;26(5-6):293-301. [Medline].
Herman MI, Chyka PA, Butler AY, Rieger SE. Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med. Jan 1999;33(1):111-3. [Medline].
Howland MA. Methylene blue. In: Goldfrank's Toxicologic Emergencies. 8th ed. 2006:1746-1748.
Price D. Methemoglobin inducers. In: Goldfrank's Toxicologic Emergencies. 8th ed. 2006:1734-1745.
Umbreit J. Methemoglobin--it's not just blue: a concise review. Am J Hematol. Feb 2007;82(2):134-44. [Medline].
Further Reading
Keywords
methemoglobinemia, red blood cells, hemoglobin, methemoglobin levels, methemoglobin, hexose-monophosphate shunt pathway, diaphorase I, diaphorase II, heme group, iron, oxidation of iron, nicotinamide adenine dinucleotide, NADH, nicotinamide adenine dinucleotide phosphate, NADPH, methylene blue, cellular hypoxia, cyanosis, discoloration of skin, acidosis
